Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is a general anesthetic used by anesthesiologists, veterinarians, and researchers. Usually, ketamine is administered intramuscularly (i.m.) or intravenously (i.v.) for induction of anesthesia. Presently, only ketamine for injection is available for administration (Physician's Desk Reference). Nasal administration of ketamine, in one instance with midazolam, for an ophthalmic procedure, and prior to elective surgery in healthy children, has been reported (Louon et al., 1993, Br. J. Ophthalmol. 77:529-530; Weksler et al., 1993, Can. J. Anaesthesia 40:119-121).
Ketamine has also been known to have analgesic properties (Domino et al., 1965, Clin. Pharmacol. Ther. 6:279); analgesia can be achieved with subanesthetic doses of ketamine (Bovill, 1971, Br. J. Anaesth. 43:496; Sadove et al., 1971, Anesth. Analg. 50:452-457). The drug is administered by various routes, including i.v., i.m., caudal, intrathecal, and subcutaneous (s.c.). Subcutaneous administration of ketamine has been used to treat pain following surgery and associated with terminal cancer (see, e.g., Oshima et al., 1990, Can. J. Anaesth. 37:385-386). Ketamine hydrochloride administered via a subcutaneous cannula was reported to successfully treat phantom limb pain (Stannard and Porter, 1993, Pain 54:227-230).
Management of pain, and particularly chronic pain, is complex and frequently unsuccessful. The first line of treatment usually involves administration of .mu.-opioid agonists, e.g., narcotics such as morphine (see, e.g., Anderson and Brill, 1992, Semin. Anesth. 11:158-171). However, rarely do physicians engage in aggressive pain management. Undertreatment for pain frequently leads to conditions where patients are forced to suffer pain up to the point of tolerability before receiving medication, and the medication is usually only partially effective. Ineffective pain management is a consequence of lack of training, and of fear of narcotics on the part of patients, the medical personnel, and society in general. Children, because of their natural reticence and budding communication skills combined with a greater fear of over-administering "dangerous" narcotics particularly suffer from under treatment for pain.
Moreover, rapid tolerance and marked resistance to narcotics frequently develop, thus rendering these agents ineffective (see, e.g., Abram, 1993, Reg. Anesth. 18(SUPPL):406-413). Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, have been reported to interfere with the development of tolerance to the analgesic effects of morphine, possibly through blockade of the NMDA receptor rather than from "side-effects" of the antagonist, since the antagonists were not found to reverse tolerance (Trujillo and Akil, 1994, Brain Res. 633:178-188).
Often, pain management involves administration of a plethora of drugs, such as narcotics, agonist-antagonist agents, butorphanols, benzodiazepines, GABA stimulators, barbiturates, barbiturate-like drugs, orally, e.g., in a pill or liquid formulation, or by i.v. or i.m. injection. Opioid agonists and antagonists may be combined. Thus, a combination of drugs can have offsetting effects. More problematic is the possibility of adverse side effects, particularly gastric distress that accompanies oral administration, or the fear that injections can inspire.
Frequently, a patient suffering from chronic pain will require medication to control stomach and other gastric problems as a result of oral administration of drugs. Alternatives to oral self-administration for most of the analgesic and sedative medications for the treatment of chronic pain are not common, can be cumbersome (e.g., i.v. or s.c. administration requires use of a cannula or needle), and generally require medical training.
U.S. Pat. No. 4,671,953 describes the administration of sedative, analgesic or sedative drugs in a candy matrix, such that the drug enters the bloodstream through the oral mucosal membranes. However, this method suffers from the disadvantage that a sedated patient may fall asleep with the candy remaining in his or her mouth, which can result in choking. Furthermore, because the total dose of the drug in the candy may exceed the desired dose, administration of the candy must be medically supervised. Finally, the candy is simply unsuitable for everyday use, as sucking on a lollipop is an unseemly practice for an employee or business person.
Moreover, when administration is under the control of the patient suffering from pain, i.e., on an outpatient basis, the potential for overdosing or abuse exists, particularly with respect to narcotics.
Thus, there is a need in the art for self-management of pain using non-opioid drugs.
There is a further need in the art for a rapid method for reducing or eliminating breakthrough pain that is refractory to standard treatment regimens.
There is a further need in the art to avoid injection administration of pain medication.
There is a need in the art for a fast, convenient, and socially acceptable method for patient self-administration of medication to manage or control pain.
There is yet a further need in the art to avoid overdose and abuse of self-administered medication, and to enhance the effectiveness of pain medications, particularly narcotic pain medication.
These and other needs in the art have been addressed by the instant invention, which is based on the inventor's discovery that ketamine can surprisingly be administered nasally to alleviate pain safely and effectively, in conjunction with or independently of other pain management regimens.
The citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.